Michail Alevizakos

Colonisation with extended-spectrum β-lactamase-producing Enterobacteriaceae and risk for infection among patients with solid or haematological malignancy: a systematic review and meta-analysis

Cancer patients are vulnerable to infections, including those with extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE), and most of these infections are associated with colonisation of the gastrointestinal tract. The aim of this study was to estimate the prevalence of gastrointestinal colonisation with ESBL-PE cancer populations and to determine the risk for subsequent bloodstream infection (BSI) with these pathogens. PubMed and EMBASE databases were searched from 1 January 1991 to 1 March 2016 to identify studies regarding ESBL-PE colonisation among patients with malignancies. Ten studies (out of 561 non-duplicate articles) were included, providing data on 2211 patients. The pooled prevalence of ESBL-PE colonisation was 19% [95% confidence interval (CI) 8-32%]. Stratifying per region, the pooled prevalence in Europe was 15% (95% CI 10-21%), whereas in Asia the pooled prevalence was 31% (95% CI 4-69%). In addition, the pooled prevalence was 15% (95% CI 7-24%) among patients with haematological malignancy, whereas no studies were identified that included solely patients with solid tumours. Notably, cancer patients with ESBL-PE colonisation were 12.98 times (95% CI 3.91-43.06) more likely to develop a BSI with ESBL-PE during their hospitalisation compared with non-colonised patients. We found that, overall, one in five patients with cancer is colonised with ESBL-PE and the incidence can be as high as one in three in Asia. This is important because colonisation was associated with an almost 13 times higher risk for developing BSI with ESBL-PE. Screening measures should be evaluated to identify their clinical benefit in patients with malignancy.

Vancomycin-resistant enterococci colonisation, risk factors and risk for infection among hospitalised paediatric patients: a systematic review and meta-analysis

The objective of this study was to estimate the rate and significance of colonisation with vancomycin-resistant enterococci (VRE) among hospitalised children. The PubMed and EMBASE databases were systematically searched (last accessed on 29 May 2016) to identify studies evaluating VRE colonisation of the gastrointestinal tract of hospitalised children in non-outbreak periods. Of 945 non-duplicate citations, 19 studies enrolling 20 234 children were included. The overall and paediatric intensive care unit (PICU) rate of VRE colonisation were both 5% [95% confidence interval (CI) 3-8% overall and 95% CI 2-9% in the PICU] but was 23% in haematology/oncology units (95% CI 18-29%). Studies that were exclusively performed in haematology/oncology units reported significantly higher rates compared with all other studies in the univariate and multivariate analyses (P = 0.001). Previous vancomycin [risk ratio (RR) = 4.34, 95% CI 2.77-6.82] or ceftazidime (RR = 4.15, 95% CI 2.69-6.40) use was a risk factor for VRE colonisation. Importantly, VRE colonisation increased the risk of subsequent VRE infection (RR = 8.75, 95% CI 3.19-23.97). In conclusion, a high rate of VRE colonisation was found among hospitalised children in institutions that performed targeted screening. Importantly, colonised children were almost 9 times more likely to develop subsequent VRE infection. Judicious use of specific antibiotics along with intensification of infection control measures should be considered in high-prevalence institutions. Also, the high incidence of VRE colonisation among children with haematological/oncological diseases identifies a high-risk population.

The salivary microbiome is consistent between subjects and resistant to impacts of short-term hospitalization

In recent years, a growing amount of research has begun to focus on the oral microbiome due to its links with health and systemic disease. The oral microbiome has numerous advantages that make it particularly useful for clinical studies, including non-invasive collection, temporal stability, and lower complexity relative to other niches, such as the gut. Despite recent discoveries made in this area, it is unknown how the oral microbiome responds to short-term hospitalization. Previous studies have demonstrated that the gut microbiome is extremely sensitive to short-term hospitalization and that these changes are associated with significant morbidity and mortality. Here, we present a comprehensive pipeline for reliable bedside collection, sequencing, and analysis of the human salivary microbiome. We also develop a novel oral-specific mock community for pipeline validation. Using our methodology, we analyzed the salivary microbiomes of patients before and during hospitalization or azithromycin treatment to profile impacts on this community. Our findings indicate that azithromycin alters the diversity and taxonomic composition of the salivary microbiome; however, we also found that short-term hospitalization does not impact the richness or structure of this community, suggesting that the oral cavity may be less susceptible to dysbiosis during short-term hospitalization.

Prevalence of ESBL-Producing Enterobacteriaceae in Pediatric Bloodstream Infections: A Systematic Review and Meta-Analysis

Background Pediatric bloodstream infections (BSIs) with Extended-Spectrum Beta-Lactamase- producing Enterobacteriaceae (ESBL-PE) are associated with worse clinical outcomes. We aimed to estimate the prevalence of and the mortality associated with ESBL-PE in this patient population. Methods A systematic review and meta-analysis using PubMed and EMBASE and included studies reporting the prevalence of ESBL-PE among confirmed BSIs in patients <19 years old. Results Twenty three (out of 1,718 non-duplicate reports) studies that provided data on 3,381 pediatric BSIs from 1996 to 2013 were included. The prevalence of ESBL-PE was 9% [95%CI (6, 13)] with an annual increase of 3.2% (P = 0.04). The prevalence was 11% [95%CI (6, 17)] among neonates, compared to 5% [95%CI (0, 14)] among children older than 28 days. The pooled prevalence was 15% in Africa [95%CI (8, 23)], 12% in South America [95%CI (5, 23)], 11% in India [95%CI (7, 17)], 7% in the rest of Asia [95%CI (0, 22)], 4% in Europe [95%CI (1, 7)] and 0% in Oceania [95%CI (0, 3)]. Importantly, the mortality in neonates with BSI due to ESBL-PE was 36% [95%CI (22, 51)], compared to 18% [95%CI (15, 22)] among all other neonates with BSI and this difference was statistically significant (P = 0.01). Conclusions In the pediatric population, the prevalence of BSI due to ESBL-PE is significant and is associated with increased mortality in neonates. Further studies are warranted to establish a high-risk group and the evaluation of preventive measures, such as antibiotic stewardship programs and infection control measures, in this population is urgently needed.

Comparison Between Carbapenems and β-Lactam/β-Lactamase Inhibitors in the Treatment for Bloodstream Infections Caused by Extended-Spectrum β-Lactamase-Producing Enterobacteriaceae: A Systematic Review and Meta-Analysis.

Abstract Background Carbapenems are widely used for the management of bloodstream infections (BSIs) caused by extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE). However, the wide use of carbapenems has been associated with carbapenem-resistant Enterobacteriaceae development. Methods We searched the PubMed and Scopus databases (last search date was on June 1, 2016) looking for studies that reported mortality in adult patients with ESBL-PE BSIs that were treated with carbapenems or β-lactam/β-lactamase inhibitors (BL/BLIs). Results Fourteen studies reported mortality data in adult patients with ESBL-PE BSI that were treated with carbapenems or BL/BLIs. Among them, 13 studies reported extractable data on empiric therapy, with no statistically significant difference in mortality of patients with ESBL-PE BSI that were treated empirically with carbapenems (22.1%; 121 of 547), compared with those that received empiric BL/BLIs (20.5%; 109 of 531; relative risk [RR], 1.05; 95% confidence interval [CI], 0.83–1.37; I2 = 20.7%; P = .241). In addition, 7 studies reported data on definitive therapy. In total, 767 patients (79.3%) received carbapenems and 199 patients (20.6%) received BL/BLIs as definitive therapy, and there was again no statistically significant difference (RR, 0.62; 95% CI, 0.25–1.52; I2 = 84.6%; P < .001). Regarding specific pathogens, the use of empiric BL/BLIs in patients with BSI due to ESBL-Escherichia coli was not associated with a statistically significant difference in mortality (RR, 1.014; 95% CI, 0.491–2.095; I2 = 62.5%; P = .046), compared with the use of empiric carbapenems. Conclusions These data do not support the wide use of carbapenems as empiric therapy, and BL/BLIs might be effective agents for initial/empiric therapy for patients with BSI caused by likely ESBL-PE, and especially ESBL-E coli.

The Attributable Burden of Clostridium difficile Infection to Long-Term Care Facilities Stay: A Clinical Study

Advanced age, history of hospitalization, and antibiotic consumption are associated with the pathogenesis of Clostridium difficile infection (CDI). Long‐term care facilities (LTCFs) represent a setting where CDI has been increasingly reported. We aimed to estimate the actual attributable burden of CDI to LTCF stay and determine the characteristics of the disease epidemiology in this setting.

Extended-spectrum β-lactamase-producing Enterobacteriaceae colonisation in long-term care facilities: a systematic review and meta-analysis

The objectives of this study were to estimate the colonisation rate by extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE) among residents of long-term care facilities (LTCFs) and to identify pertinent risk factors. A systematic search of PubMed and EMBASE databases for studies published up to May 2016 that provided raw data for gastrointestinal colonisation by ESBL-PE among LTCF residents was performed. Twenty-three studies reporting data on 9775 screened subjects met the inclusion criteria. The pooled prevalence of ESBL-PE among LTCF residents was 18% [95% confidence interval (CI) 12-24%]. Risk factors for colonisation included recent antibiotic use (within 6 months) [odds ratio (OR) = 2.06, 95% CI 1.78-2.38], previous hospitalisation (within 2.5 years) (OR = 1.50, 95% CI 1.04-2.15), history of invasive procedures (within 2 years) (OR = 2.79, 95% CI 1.66-4.70), previous ESBL-PE colonisation or infection (OR = 6.77, 95% CI 1.33-34.62), history of urinary tract infection (OR = 2.66, 95% CI 1.76-4.01) and urinary catheter use (OR = 2.55, 95% CI 1.29-5.04). In conclusion, almost one in five LTCF residents is colonised with ESBL-PE, and colonised residents are more likely to have a history of recent antibiotic use or healthcare facility utilisation. Strict adherence to antimicrobial stewardship in LTCFs is needed to address these high resistance rates.

The Dose-Dependent Efficacy of Cefepime in the Empiric Management of Febrile Neutropenia: A Systematic Review and Meta-Analysis

Abstract Background Despite reports questioning its efficacy, cefepime remains a first-line option in febrile neutropenia. We aimed to re-evaluate the role of cefepime in this setting. Methods We searched the PubMed and EMBASE databases to identify randomized comparisons of (1) cefepime vs alternative monotherapy or (2) cefepime plus aminoglycoside vs alternative monotherapy plus aminoglycoside, published until November 28, 2016. Results Thirty-two trials, reporting on 5724 patients, were included. Clinical efficacy was similar between study arms (P = .698), but overall mortality was greater among cefepime-treated patients (risk ratio [RR] = 1.321; 95% confidence interval [CI], 1.035–1.686; P = .025). Also of note, this effect seemed to stem from trials using low-dose (2 grams/12 hours, 100 mg/kg per day) cefepime monotherapy (RR = 1.682; 95% CI, 1.038–2.727; P = .035). Cefepime was also associated with increased mortality compared with carbapenems (RR = 1.668; 95% CI, 1.089–2.555; P = .019), a finding possibly influenced by cefepime dose, because carbapenems were compared with low-dose cefepime monotherapy in 5 of 9 trials. Treatment failure in clinically documented infections was also more frequent with cefepime (RR = 1.143; 95% CI, 1.004–1.300; P = .043). Toxicity-related treatment discontinuation was more common among patients that received high-dose cefepime (P = .026), whereas low-dose cefepime monotherapy resulted in fewer adverse events, compared with alternative monotherapy (P = .009). Conclusions Cefepime demonstrated increased mortality compared with carbapenems, reduced efficacy in clinically documented infections, and higher rates of toxicity-related treatment discontinuation. The impact of cefepime dosing on these outcomes is important, because low-dose regimens were associated with lower toxicity at the expense of higher mortality.

Malignant and borderline epithelial ovarian tumors in the pediatric and adolescent population

OBJECTIVES Malignant and borderline ovarian tumors of epithelial origin are rarely encountered among prepubertal girls and adolescents. The aim of this population-based study was to elucidate their clinicopathological characteristics and prognosis using a multi-institutional tumor registry. STUDY DESIGN AND OUTCOMES The National Cancer Institutes Surveillance, Epidemiology, and End Results database was accessed and a cohort of females aged <=19years old, diagnosed between 1988 and 2013 with a borderline ovarian tumor (BOT) or a malignant epithelial ovarian carcinoma (EOC) was accessed. Observed survival (OS) was assessed using the Kaplan-Meier method. Comparisons were made using the log-rank test. RESULTS A total of 114 cases diagnosed with BOT between 1988 and 2000 were identified; 61/114 (53.5%) and 51/114 (44.8%) of BOT were of serous or mucinous histology respectively. Ten-year OS for those with BOT was 97.3%. A total of 140 cases of EOC were identified. Median age was 17 years and the most common histological subtypes were mucinous 79/140 (56.4%) and serous 29/140 (20.7%) adenocarcinoma. Most had stage I disease 92/131 (70.2%) and fertility-sparing surgery was commonly performed. Five-year OS for those with stage I disease was 93.6% compared to 48.3% for cases with exta-ovarian tumor spread (p<0.001). CONCLUSIONS BOT and EOC are exceedingly rare in the pediatric and adolescent population. In this age group EOC consists mostly of low-grade mucinous and serous tumors confined to the ovary. OS survival for those with stage I disease is excellent.

Bloodstream infections due to extended-spectrum β-lactamase-producing Enterobacteriaceae among patients with malignancy: a systematic review and meta-analysis

Extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE) are an increasing cause of resistant infections among patients with malignancy. This study sought to estimate the prevalence of bloodstream infections (BSIs) caused by ESBL-PE in this population and to examine regional and temporal differences. The PubMed and EMBASE databases (to 30 April 2016) were searched to identify studies reporting ESBL-PE BSI rates among patients with malignancies. Of 593 non-duplicate reports, 22 studies providing data on 5650 BSI cases satisfied the inclusion criteria. Among all BSIs the pooled prevalence of ESBL-PE was 11% (95% CI 8-15%) and among Gram-negative BSIs it was 21% (95% CI 16-27%). Among patients with haematological malignancies, the pooled ESBL-PE prevalence was 11% (95% CI 8-15%), whereas no studies providing specific data on patients with solid tumours were identified. Stratifying per geographic region, the pooled prevalence was 7% each in Europe (95% CI 5-11%), the Eastern Mediterranean region (95% CI 4-11%) and South America (95% CI 2-14%), 10% in the Western Pacific region (95% CI 4-19%) and 30% in Southeast Asia (95% CI 18-44%). Importantly, there was a 7.1% annual increase in the ESBL-PE incidence (P = 0.004). Overall, ca. 1 in 10 BSIs in patients with malignancy is caused by ESBL-PE and in some areas this rate can be as high as 1 in 3 cases. Additionally, the incidence of these resistant infections is rising. These findings should be considered when selecting empirical antimicrobial therapy and should prompt strict adherence to antimicrobial stewardship.